The residents of the study area, approximately 8000 people aged at least 5 years, have participated in a longitudinal population study since 1965, allowing study of the risk factors and effects of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on development of vascular complications and mortality. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose regulation, occupational and leisure-time physical activity and diabetes in relatives are assessed. Findings on risk factors for diabetes are applied to a multicenter randomized clinical trial of prevention of type 2 diabetes that is currently in a long-term outcomes phase (the Diabetes Prevention Program Outcomes Study). Studies of the genetics of type 2 diabetes, obesity, and diabetes complications are described in other projects.[unreadable] [unreadable] Although it had been previously hypothesized that impairment in insulin secretion was a relatively late physiologic abnormality predisposing to type 2 diabetes in person with insulin resistance, long-term follow-up of persons undergoing measurements of insulin secretion and sensitivity while they still had normal glucose regulation showed that even this early in the disease process, impairments in both insulin secretion and sensitivity are important long-term predictors of diabetes. Mathematical modeling of changes in plasma glucose concentration during decades preceding the onset of diabetes suggests that the onset of diabetes occurs relatively rapidly, i.e., within two to three years, rather than as a result of gradual, but linear, rises in glucose concentrations over many years. This finding suggests that diabetes screening may need to occur more often than every two to three years, and that research on the events leading to onset of diabetes might focus on a period of a few years before disease onset. Despite the very high incidence rates of diabetes in Pima Indians, during the last 40 years the age-specific incidence rates in adult Pima Indians have been relatively constant, implying that the high rates experienced today are not primarily the result of recent environmental or social change.[unreadable] [unreadable] Knowledge of diabetes risk factors coming from this and other studies led to the hypothesis that type 2 diabetes could be prevented or delayed in adults at high short-term risk. This hypothesis was confirmed in the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial in which many of the participants and investigators in this project participated. We are now in a long-term follow-up phase, the Diabetes Prevention Program Outcomes Study (DPPOS), to assess long-term success with weight loss, reduction in the incidence of diabetes, and effects on diabetes complications. The DPPOS also began a genetics component to test whether genes with known or suspected effects on type 2 diabetes affected diabetes incidence in the DPP and interacted with study interventions. The recently discovered diabetes-associated gene, TCF7L2, was confirmed to predict onset of diabetes in the DPP. Furthermore, the intensive lifestyle weight-loss intervention led to a greater reduction in diabetes incidence in those participants with the high-risk genotype at TCF7L2, an example of a genotype-treatment interaction in diabetes prevention.